EP4176880A1 - Pharmaceutical composition for preventing or treating cancer comprising 3-ketoacyl-coa thiolase inhibitor and carnitine acylcarnitine carrier inhibitor - Google Patents

Pharmaceutical composition for preventing or treating cancer comprising 3-ketoacyl-coa thiolase inhibitor and carnitine acylcarnitine carrier inhibitor Download PDF

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EP4176880A1
EP4176880A1 EP21831511.7A EP21831511A EP4176880A1 EP 4176880 A1 EP4176880 A1 EP 4176880A1 EP 21831511 A EP21831511 A EP 21831511A EP 4176880 A1 EP4176880 A1 EP 4176880A1
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Prior art keywords
inhibitor
cancer
acaa
cac
halogen
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German (de)
English (en)
French (fr)
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EP4176880A4 (en
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Sooyoul KIM
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New Cancer Cure Bio Co Ltd
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National Cancer Center
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating cancer, or an anticancer adjuvant, comprising a 3-ketoacyl CoA thiolase inhibitor and a Carnitine Acylcarnitine Carrier inhibitor.
  • Normal cells are capable of regular and elastic proliferation and inhibition as needed, whereas cancer cells proliferate indefinitely, which is a cell mass composed of undifferentiated cells, also called tumor. These cancer cells invade the surrounding tissues and metastasize to other organs in the body, causing severe pain and eventually death.
  • cancer cells proliferate indefinitely, which is a cell mass composed of undifferentiated cells, also called tumor. These cancer cells invade the surrounding tissues and metastasize to other organs in the body, causing severe pain and eventually death.
  • the number of cancer patients in Korea has increased continuously and has increased by about 44% over the past 10 years.
  • first-generation anticancer agents There were first-generation anticancer agents, chemical anticancer agents, and second-generation, targeted anti-cancer agents.
  • immuno-oncology agents have been developed as third-generation anti-cancer agents, and research is being conducted continuously.
  • the biggest problem in current cancer treatment is the recurrence of cancer because there are various mutations in the cancer, making it difficult to target a specific cancer, and resistance to the anticancer drugs used in the treatment of relapsed cancer occurs. After all, even after treating the primary cancer, most of the patients die due to metastasis and recurrent cancer. Accordingly, in order to enhance the effect of anticancer drugs, a strategy for combining anticancer drugs and treating them in combination has been proposed.
  • Trimetazidine a 3-ketoacyl CoA thiolase (ACAA) inhibitor
  • ACAA an anti-ischemic (anti-angina) metabolizer or fatty acid oxidation inhibitor
  • Omeprazole a Carnitine Acylcarnitine Carrier (CAC) inhibitor
  • CAC Carnitine Acylcarnitine Carrier
  • Korean Patent Laid-Open Patent No. 10-2020-0041806 discloses a pharmaceutical composition for preventing or treating cancer comprising a malate-aspartate shuttle inhibitor and carnitine acylcarnitine carrier inhibitor, and it is described that the types of carnitine acylcarnitine carrier inhibitor include trimetazidine or omeprazole.
  • the present inventors have made intensive efforts to provide a combination anticancer agent capable of significantly inhibiting cancer cells, and as a result, when a 3-ketoacyl CoA thiolase inhibitor and a carnitine acylcarnitine carrier inhibitor were treated in combination, it was confirmed that the cancer cell inhibitory effect was significantly increased compared to the case where each inhibitor was treated alone, and the present invention was completed.
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, or an anti-cancer adjuvant comprising a 3-ketoacyl CoA thiolase inhibitor and a carnitine acylcarnitine carrier inhibitor.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a 3-ketoacyl CoA thiolase (ACAA) inhibitor and a Carnitine Acylcarnitine Carrier (CAC) inhibitor represented by Formula 1 below: wherein, R 1 to R 4 are each independently H, C 1-6 alkyl substituted or unsubstituted with one or more halogen, or C 1-6 alkoxy substituted or unsubstituted with one or more halogen, and wherein halogen is selected from the group consisting of F, Cl, Br, and I.
  • AZA 3-ketoacyl CoA thiolase
  • CAC Carnitine Acylcarnitine Carrier
  • the present invention provides an anticancer adjuvant comprising a 3-ketoacyl CoA thiolase (ACAA) inhibitor and a Carnitine Acylcarnitine Carrier (CAC) inhibitor represented by Formula 1 above.
  • ACAA 3-ketoacyl CoA thiolase
  • CAC Carnitine Acylcarnitine Carrier
  • the ACAA inhibitor may be trimetazidine (KN713), ranolazine (KN715), or a pharmaceutically acceptable salt thereof.
  • the CAC inhibitor may be omeprazole (KN510), lansoprazole (KN511), pantoprazole (KN512), or a pharmaceutically acceptable salt thereof.
  • the ACAA inhibitor and the CAC inhibitor may be included in a concentration ratio of 1: 100 to 100: 1.
  • the ACAA inhibitor and the CAC inhibitor may be administered sequentially or simultaneously.
  • the cancer may include one or more selected from the group consisting of colon cancer, lung cancer, stomach cancer, breast cancer, brain cancer, melanoma, glioblastoma, prostate cancer, ovarian cancer, kidney cancer, pancreatic cancer, blood cancer, and liver cancer.
  • the pharmaceutical composition or anticancer adjuvant may further include an additional anticancer agent.
  • the additional anticancer agent may be irinotecan, paclitaxel, capecitabine (5-fu), gemcitabine, vemurafenib, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for preventing or treating cancer comprising administering or taking a composition comprising a 3-ketoacyl CoA thiolase (ACAA) inhibitor and a Carnitine Acylcarnitine Carrier (CAC) inhibitor represented by Formula 1 above as an active ingredient to an individual.
  • ACAA 3-ketoacyl CoA thiolase
  • CAC Carnitine Acylcarnitine Carrier
  • the present invention provides a use of a composition for preventing or treating cancer comprising a 3-ketoacyl CoA thiolase (ACAA) inhibitor and a Carnitine Acylcarnitine Carrier (CAC) inhibitor represented by Formula 1 above as an active ingredient.
  • ACAA 3-ketoacyl CoA thiolase
  • CAC Carnitine Acylcarnitine Carrier
  • the present composition comprising a 3-ketoacyl CoA thiolase and a carnitine acylcarnitine carrier inhibitor can be provided as an effective combination anticancer agent because the growth of cancer cells, oxygen consumption and tumor size are significantly reduced compared to when a 3-ketoacyl CoA thiolase or a carnitine acylcarnitine carrier inhibitor is used alone, respectively.
  • the conventional anticancer drugs used for cancer treatment have problems in that side effects and drug resistance are likely to occur, so the development of anticancer targeted therapeutics as an alternative thereto is required.
  • the present composition comprising a 3-ketoacyl CoA thiolase and a carnitine acylcarnitine carrier inhibitor can be provided as an effective combination anticancer agent because the growth of cancer cells, oxygen consumption and tumor size are significantly reduced compared to when a 3-ketoacyl CoA thiolase or a carnitine acylcarnitine carrier inhibitor is used alone, respectively.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a 3-ketoacyl CoA thiolase (ACAA) inhibitor and a Carnitine Acylcarnitine Carrier (CAC) inhibitor represented by Formula 1 below: wherein, R 1 to R 4 are each independently H, C 1-6 alkyl substituted or unsubstituted with one or more halogen, or C 1-6 alkoxy substituted or unsubstituted with one or more halogen, and wherein halogen is selected from the group consisting of F, Cl, Br, and I.
  • AZA 3-ketoacyl CoA thiolase
  • CAC Carnitine Acylcarnitine Carrier
  • the ACAA inhibitor may be trimetazidine (KN713), ranolazine (KN715), or a pharmaceutically acceptable salt thereof.
  • the CAC inhibitor may be omeprazole (KN510), lansoprazole (KN511), pantoprazole (KN512), or a pharmaceutically acceptable salt thereof.
  • the ACAA inhibitor and the CAC inhibitor may be included in a concentration ratio of 1: 100 to 100: 1.
  • the ACAA inhibitor and the CAC inhibitor may be administered sequentially or simultaneously.
  • the cancer may be selected from the group consisting of colon cancer, lung cancer, stomach cancer, breast cancer, brain cancer, melanoma, glioblastoma, prostate cancer, ovarian cancer, kidney cancer, pancreatic cancer, blood cancer, and liver cancer.
  • composition of the present invention may be in various oral or parenteral formulations.
  • it can be formulated using one or more buffers (e.g., saline or PBS), antioxidants, bacteriostatic agents, chelating agents (e.g., EDTA or glutathione), fillers, bulking agents, binders, adjuvants (e.g., aluminum hydroxide), suspending agent, thickening agent, wetting agents, disintegrating agents or surfactants, diluents or excipients.
  • buffers e.g., saline or PBS
  • antioxidants e.g., bacteriostatic agents, chelating agents (e.g., EDTA or glutathione)
  • fillers e.g., bulking agents, binders, adjuvants (e.g., aluminum hydroxide), suspending agent, thickening agent, wetting agents, disintegrating agents or surfactants, diluents or excipients.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in one or more compounds, for example, starch (corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose or gelatin are mixed and prepared.
  • starch corn starch, wheat starch, rice starch, potato starch, etc.
  • calcium carbonate sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose or gelatin are mixed and prepared.
  • lubricants such as magnesium stearate and talc may be also used.
  • Liquid formulations for oral administration include suspensions, internal solutions, emulsions, or syrups.
  • various excipients such as wetting agents, sweetening agents, fragrances or preservatives may be included.
  • cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant, and an anti-aggregant, lubricant, wetting agent, flavoring agent, emulsifier and preservative may be additionally included.
  • the formulations for parenteral administration include sterile aqueous solutions, nonaqueous solutions, suspensions, emulsions, lyophilized formulations, or suppositories.
  • nonaqueous solvents and suspensions propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used.
  • injectable esters such as ethyl oleate
  • witepsol, macrogol, tween 61, cacao butter, laurin fat, glycerol, gelatin, etc. can be used as a base of the suppository.
  • composition of the present invention may be administered orally or parenterally, and when administered parenterally, for external use; It can be formulated according to a method known in the art in the form of an injection for intraperitoneal, rectal, intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection.
  • suitable carriers may include, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof, and/or a solvent or dispersion medium containing vegetable oil. More preferably, suitable carriers, such as, Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) or sterile water for injection with triethanolamine, isotonic solutions such as 10% ethanol, 40% propylene glycol and 5% dextrose, etc. can be used.
  • PBS phosphate buffered saline
  • isotonic solutions such as 10% ethanol, 40% propylene glycol and 5% dextrose, etc.
  • the injection may further include various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • the injection may further contain an isotonic agent such as sugar or sodium chloride.
  • composition of the present invention can be administered in a pharmaceutically effective amount.
  • a pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level refers to the patient's disease type, severity, drug activity, drug sensitivity, and administration time, route of administration and excretion rate, duration of treatment, factors including concomitant drugs, and other factors well known in the medical field.
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple.
  • the total effective amount of the composition of the present invention may be administered to a patient as a single dose, and may be administered by a fractionated treatment protocol in which multiple doses are administered for a long period of time.
  • a fractionated treatment protocol in which multiple doses are administered for a long period of time.
  • the preferred dosage of the composition varies depending on the patient's condition, body weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, for example, 0.0001 to 2,000 mg/kg per day, more preferably, it may be administered at 0.001 to 2,000 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. However, the scope of the present invention is not limited by the dosage.
  • composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
  • the control used for comparison of the cancer cell suppression effect may be a medium treated with a vehicle solvent, and the vehicle may be DW (1%), DMSO (0.1% to 0.2%) or SMSO (0.1%).
  • the present invention can provide an anticancer adjuvant comprising a 3-ketoacyl CoA thiolase (ACAA) inhibitor and a Carnitine Acylcarnitine Carrier (CAC) inhibitor represented by Formula 1 above.
  • ACAA 3-ketoacyl CoA thiolase
  • CAC Carnitine Acylcarnitine Carrier
  • the ACAA inhibitor may be trimetazidine (KN713), ranolazine (KN715), or a pharmaceutically acceptable salt thereof.
  • the CAC inhibitor may be omeprazole (KN510), lansoprazole (KN511), pantoprazole (KN512), or a pharmaceutically acceptable salt thereof.
  • the ACAA inhibitor and the CAC inhibitor may be included in a concentration ratio of 1:100 to 100:1.
  • the ACAA inhibitor and the CAC inhibitor may be administered sequentially or simultaneously.
  • the cancer may be selected from the group consisting of colon cancer, lung cancer, stomach cancer, breast cancer, brain cancer, melanoma, glioblastoma, prostate cancer, ovarian cancer, kidney cancer, pancreatic cancer, blood cancer, and liver cancer.
  • the anticancer adjuvant of the present invention refers to any form for enhancing the anticancer effect of an anticancer agent or suppressing or improving the side effects of an anticancer agent.
  • the anticancer adjuvant of the present invention may be administered in combination with various types of anticancer agents or anticancer adjuvants, and when administered in combination, even if the anticancer agent is administered at a level lower than the dose of a conventional anticancer agent, the same level of anticancer therapeutic effect can be exhibited, so safer anti-cancer treatment can be performed.
  • the administration route of the anticancer adjuvant may be administered through any general route as long as it can reach the target tissue.
  • the anticancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, orally, intrapulmonary administration, or rectal, depending on the purpose, but is not limited thereto.
  • the anticancer adjuvant may be administered by any device capable of transporting an active substance to a target cell.
  • the anticancer adjuvant of the present invention may be preferably formulated as an anticancer adjuvant by including one or more pharmaceutically acceptable carriers in addition to the active ingredient for administration.
  • Carriers, excipients or diluents that may be included in the anticancer adjuvant of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, Calcium Silicate, Cellulose, Methyl Cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, but is not limited thereto.
  • the anticancer adjuvant of the present invention may be a formulation for oral or parenteral administration, and the description of the formulation is substituted for the description of the formulation of the pharmaceutical composition.
  • Pancreatic cancer (MIA PaCa2, Capan1, Capan2, BxPC-3, SNU-213 or SNU-324) cell lines (100 ⁇ l) were seeded into 96-well microtiter plates at densities ranging from 7,500 to 10,000 cells/well depending on the doubling time of each cell line. After adding Trimetazidine (KN713) 1mM, omeprazole (KN510) 100 or 200 ⁇ M, trimetazidine 1mM + omeprazole 100 ⁇ M, trimetazidine 1mM + omeprazole 200 ⁇ M, respectively, to each well by 100 ⁇ l each, and plate was incubated in a CO 2 incubator, and cold TCA was added to terminate the assay.
  • Trimetazidine KN713
  • omeprazole KN510
  • OCR oxygen consumption rate
  • basal respiration and ATP production ATP
  • MIA PaCa-2 cell culture plates (Seahorse Bioscience, North Billerica). MIA PaCa-2 cells were each seeded at 15,000 cells/well (XF96 plate), and cultured for 24 hours in a humidified 37°C incubator of 5% CO 2 . Prior to performing the assay, the growth medium in the wells had a minimum concentration of 1: 1000, and 170 ⁇ l of the assay medium was added to the cells. While calibrating the sensor cartridge, the cell plate was incubated for 60 min in a 37°C/non-CO 2 incubator prior to the start of the assay. All experiments were performed at 37°C. Each measurement cycle consisted of a mixing time of 2 min and a data collection cycle time of 4 min.
  • Respiratory chain inhibitor of oligomycin, FCCP (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone), Rotenone & antymycin A were prepared in an appropriate concentration in the cartridge, adjusted to pH 7.4, and added to each injection port. Three baselines were measured before addition of the respiratory chain inhibitor, and three responses were measured after each addition. The OCR data points represent the average absolute velocity (pmoles /min) over the measurement period. [Table 4] shows the basal respiratory volume to ATP production in [ FIG. 4 ].
  • IACUC Institutional Animal Care and Use Committee
  • [Table 5] shows the tumor size of [ Fig. 5 ].
  • the SRB assay was performed as follows: each cell line (100 ⁇ l) was seeded into 96-well microtiter plates at densities ranging from 5,000 to 20,000 cells/well depending on the doubling time of each cell line. After cell seeding, microtiter plates were incubated for 24 h before addition of experimental drug. Drugs were prepared at the indicated concentrations and 100 ⁇ l was added to each well; The plates were then incubated in a CO 2 incubator. Then, cold TCA was added to terminate the assay. Cells were fixed in situ by gentle addition of 50 ⁇ l of cold 50% (w/v) TCA (final concentration: 10% TCA) and incubated at 4°C for 60 min.
  • Figure 7a and Table 6 show the results of analyzing the effect of the combined treatment of the CAC inhibitor KN510 (Omeprazole) and the ACAA inhibitor KN715 (Ranolazine). This is the result of treatment with Control, KN510 100 ⁇ M alone, KN510 200 ⁇ M alone, KN715 200 ⁇ M alone, KN510 100 ⁇ M + KN715 200 ⁇ M (combination treatment), KN510 200 ⁇ M + KN715 200 ⁇ M (combination treatment) in pancreatic cancer cell lines for 48 hours.
  • Figure 7b and Table 7 show the results of analyzing the effect of the combined treatment of the CAC inhibitor KN511 (Lansoprazole) and the ACAA inhibitor KN713 (Trimetazidine). This is the result of treatment with Control, KN511 50 ⁇ M alone, KN511100 ⁇ M alone, KN713 2.5 mM alone, KN511 50 ⁇ M + KN713 2.5 mM (combination treatment), KN511100 ⁇ M + KN713 2.5 mM (combination treatment) in pancreatic cancer cell lines for 48 hours.
  • Figure 7c and Table 8 show the results of analyzing the effect of the combined treatment of the CAC inhibitor KN512 (Pantoprazole) and the ACAA inhibitor KN713 (Trimetazidine). This is the result of treatment with Control, KN512 100 ⁇ M alone, KN512 200 ⁇ M alone, KN713 2.5 mM alone, KN511 50 ⁇ M + KN713 2.5 mM (combination treatment), KN512 100 ⁇ M + KN713 2.5 mM (combination treatment) in pancreatic cancer cell lines for 48 hours.
  • Figure 7d and Table 9 show the results of analyzing the effect of the combined treatment of the CAC inhibitor KN511 (Lansoprazole) and the ACAA inhibitor KN715 (Ranolazine).
  • This is the result of treatment with Control, KN511 50 ⁇ M alone, KN511100 ⁇ M alone, KN715 200 ⁇ M alone, KN511 50 ⁇ M + KN715 200 ⁇ M (combination treatment), KN511 100 ⁇ M + KN715 200 ⁇ M (combination treatment) in pancreatic cancer cell lines for 48 hours.
  • Control KN511 50 ⁇ M alone, KN511100 ⁇ M alone, KN715 200 ⁇ M alone, KN511 50 ⁇ M + KN715 200 ⁇ M (combination treatment), KN511 100 ⁇ M + KN715 200 ⁇ M (combination treatment) in pancreatic cancer cell lines for 48 hours.
  • KN511 50 ⁇ M alone KN5
  • Figure 7e and Table 10 show the results of analyzing the effect of the combined treatment of the CAC inhibitor KN512 (Pantoprazole) and the ACAA inhibitor KN715 (Ranolazine). This is the result of treatment with Control, KN512 100 ⁇ M alone, KN512 200 ⁇ M alone, KN715 200 ⁇ M alone, KN512 100 ⁇ M + KN715 200 ⁇ M (combination treatment), KN512 200 ⁇ M + KN715 200 ⁇ M (combination treatment) in pancreatic cancer cell lines for 48 hours.
  • the SRB assay was performed as follows: each cell line (100 ⁇ l) was seeded into 96-well microtiter plates at densities ranging from 5,000 to 40,000 cells/well depending on the doubling time of each cell line. After 24 hours, drug (100 ⁇ l per well) was added to each well and the culture was incubated at 37°C for 48 hours. Cells were then fixed in 50% TCA (50 ⁇ l per well) and plates were incubated at 4°C for a minimum of 1 hour or a maximum of 3 hours. After that, the liquid was removed from the plate, then rinsed 5 times with water and dried for approximately 12-24 hours at room temperature (RT).
  • RT room temperature
  • GI 50 is the maximum concentration at the moment of 50% inhibition of cell proliferation and IC 50 is the concentration of the drug that inhibits the enzyme activity in vitro by 50% in this study.

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EP21831511.7A 2020-07-01 2021-07-01 PHARMACEUTICAL COMPOSITION FOR THE PREVENTION OR TREATMENT OF CANCER WITH 3-KETOACYL-COA-THIOLASE INHIBITOR AND CARNITINACYL CARNITINE CARRIER INHIBITOR Pending EP4176880A4 (en)

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